Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
J Alzheimers Dis. 2024;101(3):787-796. doi: 10.3233/JAD-231399.
Aggregated forms of the amyloid-β (Aβ) peptides which form protofibrils and fibrils in the brain are signatures of Alzheimer's disease (AD). Aggregates are also recognized by microglia, which in early phases may be protective and in later phases contribute to the pathology. We have identified several small molecules, decoys which interfere with Aβ oligomerization and induce other aggregation trajectories leading to aggregated macrostructures which are non-toxic.
This study investigates whether the small-molecule decoys affect microglial activation in terms of cytokine secretion and phagocytosis of Aβ peptide.
The effects of the decoys (NSC 69318, NSC 100873, NSC 16224) were analyzed in a model of human THP-1 monocytes differentiated to microglia-like cells. The cells were activated by Aβ40 and Aβ42 peptides, respectively, and after treatment with each decoy the secreted levels of pro-inflammatory cytokines and the Aβ phagocytosis were analyzed.
NSC16224, which generates a double-stranded aggregate of thin protofibrils, was found to block Aβ40- and Aβ42-induced increase in microglial secretion of pro-inflammatory cytokines. NSC 69318, selective for neurotoxicity of Aβ42, and NSC 100873 did not significantly reduce the microglial activation in terms of cytokine secretion. The uptake of Aβ42 was not affected by anyone of the decoys.
Our findings open the possibility that the molecular decoys of Aβ aggregation may block microglial activation by Aβ40 and Aβ42 in addition to blocking neurotoxicity as shown previously.
在大脑中形成原纤维和纤维的淀粉样β（Aβ）肽的聚集形式是阿尔茨海默病（AD）的特征。聚集物也被小胶质细胞识别，小胶质细胞在早期可能具有保护作用，而在后期则有助于发病机制。我们已经鉴定出几种小分子，诱饵可以干扰 Aβ寡聚化并诱导其他聚集轨迹，从而导致非毒性的聚集宏观结构。
本研究调查小分子诱饵是否会影响小胶质细胞激活，包括细胞因子分泌和 Aβ肽的吞噬作用。
在人 THP-1 单核细胞分化为小胶质样细胞的模型中分析了诱饵（NSC 69318、NSC 100873、NSC 16224）的作用。用 Aβ40 和 Aβ42 肽分别激活细胞，然后分析每种诱饵处理后的细胞因子分泌水平和 Aβ的吞噬作用。
发现 NSC16224 生成薄原纤维的双链聚集物，可阻止 Aβ40 和 Aβ42 诱导的小胶质细胞促炎细胞因子分泌增加。选择性针对 Aβ42 神经毒性的 NSC 69318 和 NSC 100873 并未在细胞因子分泌方面显著降低小胶质细胞激活。没有一种诱饵能影响 Aβ42 的摄取。
我们的研究结果表明，Aβ聚集的分子诱饵可能除了阻断先前显示的神经毒性外，还可以阻止 Aβ40 和 Aβ42 引起的小胶质细胞激活。
